It is believed that induction of
cytokine expression by bacterial cell wall components plays a role in the development and course of
sepsis. However, most attention has been focused on
lipopolysaccharide (LPS). We studied the ability of N-acetylglucosaminyl-1,6-anhydro-N-acetylmuramyl-L-alanyl-D- isoglutamyl-m-diaminopimelyl-D-
alanine (
G(Anh)MTetra), a naturally occurring breakdown product of
peptidoglycan that is produced by
soluble lytic transglycosylase of Escherichia coli, to induce
cytokine expression in human monocytes.
G(Anh)MTetra was found to strongly induce
interleukin (IL)-1 beta and
IL-6 mRNA expression after 2 h and
IL-1 beta and
IL-6 protein secretion after 48 h of activation. The increase in
mRNA accumulation was at least partly due to an increase in the transcription rates of the respective genes and was accompanied by a strong induction of
nuclear factor-kappa B and
activator protein-1 transcription factor expression. Experiments using inhibitors of
protein kinase C,
protein kinase A, and
tyrosine kinase-dependent pathways revealed that
G(Anh)MTetra-induced
IL-1 beta and
IL-6 mRNA expression involves activation of an H7-inhibitable pathway. By using the
protein synthesis inhibitor cycloheximide, it was shown that
G(Anh)MTetra-induced
IL-6 mRNA expression depends on the synthesis of new
protein, whereas
G(Anh)MTetra-induced
IL-1 beta mRNA accumulation does not. When responses to
G(Anh)MTetra were compared with those to LPS and muramyldipeptide (MDP), it was found that the optimal response to
G(Anh)MTetra induction was similar to that of LPS but significantly higher than the response to MDP. Furthermore, maximal
G(Anh)MTetra-induced
IL-1 beta and
IL-6 mRNA expression could be enhanced by co-stimulation with LPS or MDP, suggesting that different receptors and/or transduction pathways were involved. These results indicate that
G(Anh)MTetra induces
IL-1 beta and
IL-6 expression in human monocytes suggesting a possible role for
G(Anh)MTetra in the release of
cytokines during
sepsis.